Colorectal Cancer (CRC)
Adenocarcinoma arising from adenomatous or sessile serrated polyps; preventable with screening.
Also known as: colon cancer, rectal cancer, colorectal cancer, CRC
Overview
Malignant neoplasm of the colon or rectum, predominantly adenocarcinoma arising from adenomatous (tubular, tubulovillous, villous) or sessile serrated polyps. Anatomic and biologic differences between right colon, left colon, and rectum influence presentation, treatment, and prognosis.
Epidemiology
Second leading cause of cancer death in the US (~150,000 new cases, ~52,000 deaths annually). 5-year survival ~65% (>90% if localized, ~15% if metastatic). Lifetime risk ~4%. Incidence falling overall due to screening, but rising in adults <50 (early-onset CRC).
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Risk factors
- Age — median diagnosis ~67 (but rising in younger adults)
- Personal or family history of CRC or adenomatous polyps
- Inherited syndromes: Lynch syndrome (HNPCC, MMR mutation), familial adenomatous polyposis (FAP, APC), MUTYH-associated polyposis, Peutz-Jeghers, juvenile polyposis
- Inflammatory bowel disease (UC > Crohn colitis); risk ~8-10 yr after diagnosis with extensive colitis
- Primary sclerosing cholangitis (synergistic with IBD)
- Diet: high red/processed meat, low fiber, low fruits/vegetables
- Smoking, heavy alcohol
- Obesity, type 2 diabetes, sedentary lifestyle
- African American ethnicity (higher incidence and mortality)
- Prior abdominal radiation
Pathophysiology
Adenoma-carcinoma sequence: normal mucosa → adenoma (APC loss) → carcinoma (KRAS, SMAD4/DPC4, TP53 mutations), taking ~10 years. Alternate serrated pathway: BRAF mutation → CpG island methylator phenotype (CIMP) → sessile serrated lesion → carcinoma. Lynch syndrome: germline mismatch repair (MLH1, MSH2, MSH6, PMS2, EPCAM) defects → microsatellite instability (MSI-H).
Clinical presentation
Symptoms
- Right-sided (cecum/ascending): occult bleeding → iron-deficiency anemia, fatigue, weight loss; large lumen tolerates mass before obstruction
- Left-sided (descending/sigmoid): change in stool caliber (narrow/pencil-thin), constipation alternating with diarrhea, hematochezia, obstruction earlier (narrower lumen)
- Rectal: hematochezia, tenesmus, rectal pain, change in bowel habit
- Systemic: weight loss, fatigue, anorexia
- Metastatic: hepatomegaly, jaundice, ascites, bone pain, cough
Signs / physical exam
- Pallor (anemia)
- Palpable abdominal mass
- Hepatomegaly if liver metastases
- Rectal mass on DRE (most rectal cancers within reach)
- Lymphadenopathy (Virchow node — rare)
- Streptococcus gallolyticus (bovis) bacteremia or endocarditis — colonoscopy mandatory
Classic findings
Older adult with iron-deficiency anemia of unclear source (right colon), or change in bowel habit with rectal bleeding (left colon/rectum).
Differential diagnosis
- Diverticulitis or diverticular disease — LLQ pain, fever; CT distinguishes; colonoscopy 6-8 wk later to exclude CRC
- Inflammatory bowel disease — Younger patient, chronic bloody diarrhea, extraintestinal manifestations
- Hemorrhoids / anal fissure — Bright red blood on toilet paper; never assume in older adult without colonoscopy
- Ischemic colitis — Sudden bloody diarrhea, watershed areas
- Infectious colitis — Acute onset, exposure, positive stool studies
- Other GI malignancies (small bowel, anal) — Imaging and biopsy
- Endometriosis (rectal) — Cyclic rectal bleeding in young women
Diagnostic workup
Diagnostic criteria
Histologic confirmation by colonoscopic biopsy. Staging by AJCC 8th edition TNM. Screening modalities (USPSTF: average-risk adults 45-75): colonoscopy every 10 yr, FIT annually, FIT-DNA (Cologuard) every 3 yr, flexible sigmoidoscopy every 5-10 yr ± FIT annually, CT colonography every 5 yr.
Labs
- CBC (microcytic anemia)
- BMP, LFTs (liver metastases)
- CEA — baseline at diagnosis; surveillance marker (not for screening)
- Iron studies
Imaging
- Colonoscopy with biopsy — DIAGNOSTIC; tattoo lesion for surgical localization
- CT chest/abdomen/pelvis with contrast — staging (M assessment)
- Rectal cancer: pelvic MRI (T and N staging), endorectal ultrasound (early T staging)
- PET-CT not routine; selected cases for equivocal metastases
- Mismatch repair (MMR) or MSI testing on all CRCs — Lynch syndrome screening and immunotherapy candidacy
- KRAS, NRAS, BRAF, HER2 testing for metastatic disease to guide therapy
Diagnostic algorithm
| Feature | Right-sided CRC | Left-sided CRC | Rectal Cancer |
|---|---|---|---|
| Typical presentation | Iron-deficiency anemia, occult bleeding, weight loss | Change in stool caliber, hematochezia, obstruction | Hematochezia, tenesmus, change in bowel habit |
| Lumen size | Wide (late obstruction) | Narrower (earlier obstruction) | Narrow |
| Molecular features | More MSI-H, BRAF V600E, CIMP | More chromosomal instability, KRAS | Similar to left colon |
| Response to anti-EGFR | Poor | Good if RAS/RAF wild-type | Variable |
| Staging imaging | CT chest/abd/pelvis | CT chest/abd/pelvis | Pelvic MRI required |
| Prognosis (stage-matched) | Worse for advanced | Better | Local recurrence higher; need TME |
Treatment
First-line
- Multidisciplinary team approach
- Stage-directed therapy (see by_subtype)
- Curative-intent surgery is the cornerstone for non-metastatic disease
- Lifestyle and risk factor counseling
Stage 0 (Tis) / Stage I (T1-T2 N0)
- Polyp with carcinoma in situ or T1: endoscopic resection with clear margins may suffice if low-risk features
- Surgical resection (segmental colectomy or low anterior resection / APR for rectum) for higher-risk lesions
- No adjuvant chemotherapy
Stage II (T3-T4 N0)
- Surgical resection with adequate lymphadenectomy (≥12 nodes)
- Adjuvant chemotherapy (5-FU-based ± oxaliplatin — FOLFOX) for high-risk Stage II (T4, perforation, obstruction, <12 nodes harvested, poorly differentiated, lymphovascular invasion, MSI-stable)
- MSI-H Stage II patients generally do NOT benefit from 5-FU monotherapy
Stage III (any T, N+)
- Surgical resection
- Adjuvant FOLFOX or CAPOX × 3-6 months
- IDEA trial: 3 months may be sufficient for low-risk Stage III (T1-3, N1)
Locally advanced rectal cancer (T3-T4 or N+)
- Total neoadjuvant therapy (TNT) — induction chemo + chemoradiation OR chemoradiation + consolidation chemo, followed by total mesorectal excision (PRODIGE 23, RAPIDO)
- Watch-and-wait approach for complete clinical responders (selective)
Stage IV (metastatic)
- Systemic therapy: FOLFOX, FOLFIRI, FOLFOXIRI ± bevacizumab (anti-VEGF) or anti-EGFR (cetuximab, panitumumab — only for RAS/RAF wild-type left-sided tumors)
- Targeted therapy by molecular profile: encorafenib + cetuximab for BRAF V600E; trastuzumab-based for HER2+; pembrolizumab/nivolumab for MSI-H/dMMR
- Metastasectomy (liver, lung) for oligometastatic disease — potentially curative
- Palliative resection/diversion/stent for obstructing tumors
Complications
- Bowel obstruction or perforation
- Fistula formation
- Anemia, hemorrhage
- Metastases — liver (most common), lung, peritoneum, ovary (Krukenberg, although gastric more classic), bone, brain
- Recurrence after curative resection (~30%)
- Treatment toxicity: oxaliplatin neuropathy, irinotecan diarrhea, 5-FU mucositis, anti-EGFR rash
PANCE pearls
- USPSTF lowered CRC screening start age to 45 in 2021 due to rising early-onset disease.
- Iron-deficiency anemia in postmenopausal women and any man requires evaluation for GI bleeding — colonoscopy + EGD.
- Streptococcus gallolyticus (S. bovis) bacteremia or endocarditis — colonoscopy is mandatory to exclude colon cancer.
- Universal MMR/MSI testing on all CRCs at diagnosis identifies Lynch syndrome AND immunotherapy candidates.
- MSI-H/dMMR metastatic CRC responds dramatically to pembrolizumab (KEYNOTE-177).
- Anti-EGFR therapy (cetuximab, panitumumab) requires RAS/RAF wild-type AND is most effective in LEFT-sided primaries.
- Bevacizumab — contraindicated for 28 days post-surgery (poor wound healing, perforation risk).
- Rectal cancer requires pelvic MRI for staging (T and N) — drives neoadjuvant therapy decisions.
- Surveillance after curative resection: CEA every 3-6 mo × 5 yr, CT chest/abdomen/pelvis annually × 5 yr, colonoscopy at 1 yr then every 3-5 yr.
- Lynch syndrome: start colonoscopy at age 20-25 every 1-2 yr; consider screening for endometrial, ovarian, gastric, urothelial cancers.
References
- USPSTF 2021 — US Preventive Services Task Force. Screening for Colorectal Cancer. JAMA 2021;325:1965-1977
- NCCN 2024 — NCCN Guidelines Version 5.2024 — Colon Cancer; Rectal Cancer
- ACG 2021 — Shaukat A et al. ACG Clinical Guidelines: Colorectal Cancer Screening 2021. Am J Gastroenterol 2021;116:458-479
- KEYNOTE-177 — André T et al. Pembrolizumab in MSI-H–Deficient Mismatch Repair Metastatic Colorectal Cancer. NEJM 2020;383:2207-2218
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